ABSTRACT— Ketones can potentiate the hepatotoxicity of haloalkanes in animals. This may be due, in part, to changes in organelle susceptibility. Male Sprague-Dawley rats were administered 15 mmol/kg (po) acetone, 2-butanone, 2-hexanone or 50 mg/kg (po) chlordecone or mirex (a nonketonic analog of chlordecone). Eighteen hours later, tests of organelle structure/function were performed (osmotic stress, respiration, and calcium pump activity). Other rats were given 14CHCl3 (0.5 or 1.0 ml/kg, po) 18 h after chlordecone or mirex administration. Three hours later, the organelle distribution of 14C was evaluated. In a final experiment, ketone-pretreated (chlordecone or 2-hexanone) animals were killed 6 h after CHCl3 administration and evaluated morphologically for evidence of modified organelle response. Acetone and chlordecone, when given alone, enhanced lysosomal fragility to osmotic stress; no changes in functional capacity of mitochondria or microsomes were observed. CHCl3-derived 14C in the mitochondrial fraction increased 2-fold in chlordecone-treated rats. Morphological evaluation suggested mitochondria respond differently to CHCl3 in ketone-pretreated (chlordecone or 2-hexanone) animals compared to corn oil-pretreated controls. These results support the concept that modifications of organelles contribute to the mechanism of ketone-potentiation of CHCl3-induced hepatotoxicity.